Sandimmune® Soft Gelatin Capsules(cyclosporine capsules ...

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SANDIMMUNE- cyclosporine capsule, liquid filled SANDIMMUNE- cyclosporine injection SANDIMMUNE- cyclosporine solution Novartis Pharmaceuticals Corporation ---------- Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) Sandimmune Oral Solution (cyclosporine oral solution, USP) Sandimmune Injection (cyclosporine injection, USP) FOR INFUSION ONLY Rx only Prescribing Information WARNING Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Sandimmune (cyclosporine). Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Sandimmune (cyclosporine) should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune Oral Solution (cyclosporine oral solution, USP) have decreased bioavailability in comparison to Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED. Sandimmune and Neoral are not bioequivalent and cannot be used interchangeably without physician supervision. The absorption of cyclosporine during chronic administration of Sandimmune Soft Gelatin Capsules and Oral Solution was found to be erratic. It is recommended that patients taking the soft gelatin capsules or oral solution over a period of time be monitored at repeated intervals for cyclosporine blood concentrations and subsequent dose adjustments be made in order to avoid toxicity due to high concentrations and possible organ rejection due to low absorption of cyclosporine. This is of special importance in liver transplants. Numerous assays are being developed to measure blood concentrations of cyclosporine. Comparison of concentrations in published literature to patient concentrations using current assays must be done with detailed knowledge of the assay methods employed (see DOSAGE AND ADMINISTRATION, Blood Concentration Monitoring). DESCRIPTION Cyclosporine, the active principle in Sandimmune (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea. Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic(L-alanyl-D-alanyl-N- methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6- octenoyl-L-α-amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl). ® ® ® ®

Transcript of Sandimmune® Soft Gelatin Capsules(cyclosporine capsules ...

SANDIMMUNE- cyclosporine capsule, liquid filled SANDIMMUNE- cyclosporine injection SANDIMMUNE- cyclosporine solution Novartis Pharmaceuticals Corporation----------Sandimmune Soft Gelatin Capsules(cyclosporine capsules, USP) Sandimmune Oral Solution(cyclosporine oral solution, USP) Sandimmune Injection(cyclosporine injection, USP) FOR INFUSION ONLY Rx only Prescribing Information

WARNINGOnly physicians experienced in immunosuppressive therapy andmanagement of organ transplant patients should prescribe Sandimmune(cyclosporine). Patients receiving the drug should be managed infacilities equipped and staffed with adequate laboratory and supportivemedical resources. The physician responsible for maintenance therapyshould have complete information requisite for the follow-up of thepatient.Sandimmune (cyclosporine) should be administered with adrenalcorticosteroids but not with other immunosuppressive agents.Increased susceptibility to infection and the possible development oflymphoma may result from immunosuppression.Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) andSandimmune Oral Solution (cyclosporine oral solution, USP) havedecreased bioavailability in comparison to Neoral Soft Gelatin Capsules(cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution(cyclosporine oral solution, USP) MODIFIED.Sandimmune and Neoral are not bioequivalent and cannot be usedinterchangeably without physician supervision.The absorption of cyclosporine during chronic administration ofSandimmune Soft Gelatin Capsules and Oral Solution was found to beerratic. It is recommended that patients taking the soft gelatin capsulesor oral solution over a period of time be monitored at repeated intervalsfor cyclosporine blood concentrations and subsequent dose adjustmentsbe made in order to avoid toxicity due to high concentrations andpossible organ rejection due to low absorption of cyclosporine. This is ofspecial importance in liver transplants. Numerous assays are beingdeveloped to measure blood concentrations of cyclosporine. Comparisonof concentrations in published literature to patient concentrations usingcurrent assays must be done with detailed knowledge of the assaymethods employed (see DOSAGE AND ADMINISTRATION, BloodConcentration Monitoring).

DESCRIPTIONCyclosporine, the active principle in Sandimmune (cyclosporine) is a cyclic polypeptideimmunosuppressant agent consisting of 11 amino acids. It is produced as a metaboliteby the fungus species Beauveria nivea.Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α-amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).

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Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) are available in25 mg and 100 mg strengths.Each 25 mg capsule contains:cyclosporine, USP…………………………………………………………………………………………25 mgalcohol, USP dehydrated………………………………………………………………max 12.7% byvolumeEach 100 mg capsule contains:cyclosporine,USP……………………………………………………………………………………….100 mgalcohol, USP dehydrated………………………………………………………………max 12.7% byvolumeInactive Ingredients: corn oil, gelatin, iron oxide red, linoleoyl macrogolglycerides,sorbitol, and titanium dioxide. May also contain glycerol. 100 mg capsules may containiron oxide yellow.Sandimmune Oral Solution (cyclosporine oral solution, USP) is available in 50 mLbottles.Each mL contains:cyclosporine,USP……………………………………………………………………………………….100 mgalcohol, Ph. Helv. ……………………………………………………………………………12.5% byvolumedissolved in an olive oil, Ph. Helv./Labrafil M 1944 CS (polyoxyethylated oleic glycerides)vehicle which must be further diluted with milk, chocolate milk, or orange juice beforeoral administration.Sandimmune Injection (cyclosporine injection, USP) is available in a 5 mL sterileampul for intravenous (IV) administration.Each mL contains:cyclosporine, USP…………………………………………………………………………………………50 mg*Cremophor EL (polyoxyethylated castor oil)………………………………………………………..650 mgalcohol, Ph. Helv. ……………………………………………………………………………32.9% byvolumenitrogen………………………………………………………………………………………………………….qswhich must be diluted further with 0.9% Sodium Chloride Injection or 5% DextroseInjection before use.The chemical structure of cyclosporine (also known as cyclosporin A) is

CLINICAL PHARMACOLOGYCyclosporine is a potent immunosuppressive agent, which in animals prolongs survival

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of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, smallintestine, and lung. Cyclosporine has been demonstrated to suppress some humoralimmunity and to a greater extent, cell-mediated reactions, such as allograft rejection,delayed hypersensitivity, experimental allergic encephalomyelitis, Freund’s adjuvantarthritis, and graft vs. host disease in many animal species for a variety of organs.Successful kidney, liver, and heart allogeneic transplants have been performed in manusing cyclosporine.The exact mechanism of action of cyclosporine is not known. Experimental evidencesuggests that the effectiveness of cyclosporine is due to specific and reversibleinhibition of immunocompetent lymphocytes in the G - or G -phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although theT-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokineproduction and release, including interleukin-2 or T-cell growth factor (TCGF).No functional effects on phagocytic (changes in enzyme secretions not altered,chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo)or tumor cells (growth rate, metastasis) can be detected in animals. Cyclosporine doesnot cause bone marrow suppression in animal models or man.The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable.Peak concentrations (C ) in blood and plasma are achieved at about 3.5 hours. Cand area under the plasma or blood concentration/time curve (AUC) increase with theadministered dose; for blood, the relationship is curvilinear (parabolic) between 0 and1400 mg. As determined by a specific assay, C is approximately 1.0 ng/mL/mg ofdose for plasma and 2.7 to 1.4 ng/mL/mg of dose for blood (for low to high doses).Compared to an intravenous infusion, the absolute bioavailability of the oral solution isapproximately 30% based upon the results in 2 patients. The bioavailability ofSandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) is equivalent toSandimmune Oral Solution, (cyclosporine oral solution, USP).Cyclosporine is distributed largely outside the blood volume. In blood, the distribution isconcentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% inlymphocytes, 5% to 12% in granulocytes, and 41% to 58% in erythrocytes. At highconcentrations, the uptake by leukocytes and erythrocytes becomes saturated. Inplasma, approximately 90% is bound to proteins, primarily lipoproteins.The disposition of cyclosporine from blood is biphasic with a terminal half-life ofapproximately 19 hours (range, 10 to 27 hours). Elimination is primarily biliary with only6% of the dose excreted in the urine.Cyclosporine is extensively metabolized but there is no major metabolic pathway. Only0.1% of the dose is excreted in the urine as unchanged drug. Of 15 metabolitescharacterized in human urine, 9 have been assigned structures. The major pathwaysconsist of hydroxylation of the Cγ-carbon of 2 of the leucine residues, Cη-carbonhydroxylation, and cyclic ether formation (with oxidation of the double bond) in the sidechain of the amino acid 3-hydroxyl-N,4-dimethyl-L-2-amino-6-octenoic acid and N-demethylation of N-methyl leucine residues. Hydrolysis of the cyclic peptide chain orconjugation of the aforementioned metabolites do not appear to be importantbiotransformation pathways.Specific PopulationsRenal ImpairmentIn a study performed in 4 subjects with end-stage renal disease (creatinine clearance <5mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hoursadministered at the end of a hemodialysis session resulted in a mean volume ofdistribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. Thissystemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL(0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysiswas 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose ofcyclosporine was recovered in the dialysate.Hepatic ImpairmentCyclosporine is extensively metabolized by the liver. Since severe hepatic impairment

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may result in significantly increased cyclosporine exposures, the dosage of cyclosporinemay need to be reduced in these patients.

INDICATIONS AND USAGESandimmune (cyclosporine) is indicated for the prophylaxis of organ rejection in kidney,liver, and heart allogeneic transplants. It is always to be used with adrenalcorticosteroids. The drug may also be used in the treatment of chronic rejection inpatients previously treated with other immunosuppressive agents.Because of the risk of anaphylaxis, Sandimmune Injection (cyclosporine injection, USP)should be reserved for patients who are unable to take the soft gelatin capsules or oralsolution.

CONTRAINDICATIONSSandimmune Injection (cyclosporine injection, USP) is contraindicated in patients with ahypersensitivity to Sandimmune (cyclosporine) and/or Cremophor EL(polyoxyethylated castor oil).

WARNINGSKidney, Liver, and Heart TransplantSandimmune (cyclosporine), when used in high doses, can cause hepatotoxicity andnephrotoxicity (see BOXED WARNING).NephrotoxicityIt is not unusual for serum creatinine and BUN levels to be elevated during Sandimmune(cyclosporine) therapy. These elevations in renal transplant patients do not necessarilyindicate rejection, and each patient must be fully evaluated before dosage adjustment isinitiated.Nephrotoxicity has been noted in 25% of cases of renal transplantation, 38% of casesof cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicitywas generally noted 2 to 3 months after transplant and consisted of an arrest in the fallof the preoperative elevations of BUN and creatinine at a range of 35 to 45 mg/dl and2.0 to 2.5 mg/dl, respectively. These elevations were often responsive to dosagereduction.More overt nephrotoxicity was seen early after transplantation and was characterized bya rapidly rising BUN and creatinine. Since these events are similar to rejection episodes,care must be taken to differentiate between them. This form of nephrotoxicity is usuallyresponsive to Sandimmune (cyclosporine) dosage reduction.Although specific diagnostic criteria which reliably differentiate renal graft rejection fromdrug toxicity have not been found, a number of parameters have been significantlyassociated to one or the other. It should be noted however, that up to 20% of patientsmay have simultaneous nephrotoxicity and rejection.

Nephrotoxicity vs. RejectionParameter Nephrotoxicity RejectionHistory Donor > 50 years old or

hypotensiveAntidonor immune response

Prolonged kidney preservation Retransplant patientProlonged anastomosis timeConcomitant nephrotoxic drugs

Clinical Often > 6 weeks postop Often < 4 weeks postopProlonged initial nonfunction(acute tubular necrosis) Fever > 37.5°C

Weight gain > 0.5 kgGraft swelling and tenderness

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p < 0.05, p < 0.01, p < 0.001, p < 0.0001.

Decrease in daily urine volume >500 mL (or 50%)

Laboratory CyA serum trough level > 200ng/mL

CyA serum trough level < 150ng/mL

Gradual rise in Cr (< 0.15mg/dL/day)

Rapid rise in Cr (> 0.3 mg/dL/day)

Cr plateau < 25% above baseline Cr > 25% above baselineBUN/Cr ≥ 20 BUN/Cr < 20

Biopsy Arteriolopathy (medialhypertrophy ,hyalinosis, nodular deposits, intimalthickening, endothelialvacuolization,progressive scarring)

Endovasculitis (proliferation ,intimal arteritis , necrosis,sclerosis)

Tubular atrophy, isometricvacuolization,isolated calcifications

Tubulitis with RBC and WBCcasts,some irregular vacuolization

Minimal edema Interstitial edema andhemorrhage

Mild focal infiltrates Diffuse moderate to severemononuclear infiltrates

Diffuse interstitial fibrosis,often striped form

Glomerulitis (mononuclear cells)

AspirationCytology

CyA deposits in tubular andendothelial cells

Inflammatory infiltrate withmononuclear phagocytes,macrophages, lymphoblastoidcells, andactivated T-cells

Fine isometric vacuolization oftubular cells

These strongly express HLA-DRantigens

Urine Cytology Tubular cells with vacuolization andgranularization

Degenerative tubular cells, plasmacells, andlymphocyturia > 20% of sediment

Manometry Intracapsular pressure < 40 mmHg

Intracapsular pressure > 40 mmHg

Ultrasonography Unchanged graft cross-sectionalarea

Increase in graft cross-sectionalareaAP diameter ≥ Transversediameter

MagneticResonanceImagery

Normal appearance Loss of distinct corticomedullaryjunction, swelling,image intensity of parachymaapproaching thatof psoas, loss of hilar fat

RadionuclideScan

Normal or generally decreasedperfusion

Patchy arterial flow

Decrease in tubular function Decrease in perfusion > decreasein tubular function

( I-hippuran) > decrease inperfusion( Tc DTPA)

Increased uptake of Indium 111labeled platelets orTc-99m in colloid

Therapy Responds to decreasedSandimmune (cyclosporine)

Responds to increased steroids orantilymphocyte globulin

A form of chronic progressive cyclosporine-associated nephrotoxicity is characterizedby serial deterioration in renal function and morphologic changes in the kidneys. From5% to 15% of transplant recipients will fail to show a reduction in a rising serumcreatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies

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from these patients will demonstrate an interstitial fibrosis with tubular atrophy. Inaddition, toxic tubulopathy, peritubular capillary congestion, arteriolopathy, and a stripedform of interstitial fibrosis with tubular atrophy may be present. Though none of thesemorphologic changes is entirely specific, a histologic diagnosis of chronic progressivecyclosporine-associated nephrotoxicity requires evidence of these.When considering the development of chronic nephrotoxicity it is noteworthy thatseveral authors have reported an association between the appearance of interstitialfibrosis and higher cumulative doses or persistently high circulating troughconcentrations of cyclosporine. This is particularly true during the first 6 posttransplantmonths when the dosage tends to be highest and when, in kidney recipients, the organappears to be most vulnerable to the toxic effects of cyclosporine. Among othercontributing factors to the development of interstitial fibrosis in these patients must beincluded, prolonged perfusion time, warm ischemia time, as well as episodes of acutetoxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and itscorrelation to renal function have not yet been determined.Impaired renal function at any time requires close monitoring, and frequent dosageadjustment may be indicated. In patients with persistent high elevations of BUN andcreatinine who are unresponsive to dosage adjustments, consideration should be givento switching to other immunosuppressive therapy. In the event of severe andunremitting rejection, it is preferable to allow the kidney transplant to be rejected andremoved rather than increase the Sandimmune (cyclosporine) dosage to a very highlevel in an attempt to reverse the rejection.Due to the potential for additive or synergistic impairment of renal function, cautionshould be exercised when coadministering Sandimmune with other drugs that mayimpair renal function (see PRECAUTIONS, Drug Interactions).Thrombotic MicroangiopathyOccasionally patients have developed a syndrome of thrombocytopenia andmicroangiopathic hemolytic anemia which may result in graft failure. The vasculopathycan occur in the absence of rejection and is accompanied by avid platelet consumptionwithin the graft as demonstrated by Indium 111 labeled platelet studies. Neither thepathogenesis nor the management of this syndrome is clear. Though resolution hasoccurred after reduction or discontinuation of Sandimmune (cyclosporine) and 1)administration of streptokinase and heparin or 2) plasmapheresis, this appears todepend upon early detection with Indium 111 labeled platelet scans (see ADVERSEREACTIONS).HyperkalemiaSignificant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis)and hyperuricemia have been seen occasionally in individual patients.HepatotoxicityCases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, andliver failure have been reported in patients treated with cyclosporine. Most reportsincluded patients with significant co-morbidities, underlying conditions and otherconfounding factors, including infectious complications and comedications withhepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes havebeen reported (see ADVERSE REACTIONS, Postmarketing Experience).Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, wasreported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation,7% in cardiac transplantation, and 4% in liver transplantation. This was usually notedduring the first month of therapy when high doses of Sandimmune (cyclosporine) wereused. The chemistry elevations usually decreased with a reduction in dosage.MalignanciesAs in patients receiving other immunosuppressants, those patientsreceiving Sandimmune (cyclosporine) are at increased risk for development oflymphomas and other malignancies, particularly those of the skin. The increased riskappears related to the intensity and duration of immunosuppression rather than to theuse of specific agents. Because of the danger of oversuppression of the immunesystem, which can also increase susceptibility to infection, Sandimmune (cyclosporine)

should not be administered with other immunosuppressive agents except adrenalcorticosteroids. The efficacy and safety of cyclosporine in combination with otherimmunosuppressive agents have not been determined. Some malignancies may be fatal.Transplant patients receiving cyclosporine are at increased risk for serious infection withfatal outcome.Serious InfectionsPatients receiving immunosuppressants, including Sandimmune, are at increased risk ofdeveloping bacterial, viral, fungal, and protozoal infections, including opportunisticinfections. These infections may lead to serious, including fatal, outcomes (see BOXEDWARNING, and ADVERSE REACTIONS).Polyoma Virus InfectionsPatients receiving immunosuppressants, including Sandimmune, are at increased risk foropportunistic infections, including polyoma virus infections. Polyoma virus infections intransplant patients may have serious, and sometimes, fatal outcomes. These includecases of JC virus-associated progressive multifocal leukoencephalopathy (PML), andpolyoma virus-associated nephropathy (PVAN), especially due to BK virus infection,which have been observed in patients receiving cyclosporine.PVAN is associated with serious outcomes, including deteriorating renal function andrenal graft loss, (see ADVERSE REACTIONS, Postmarketing Experience). Patientmonitoring may help detect patients at risk for PVAN.Cases of PML have been reported in patients treated with Sandimmune. PML, which issometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitivedeficiencies, and ataxia. Risk factors for PML include treatment with immunosuppressanttherapies and impairment of immune function. In immunosuppressed patients,physicians should consider PML in the differential diagnosis in patients reportingneurological symptoms and consultation with a neurologist should be considered asclinically indicated.Consideration should be given to reducing the total immunosuppression in transplantpatients who develop PML or PVAN. However, reduced immunosuppression may placethe graft at risk.NeurotoxicityThere have been reports of convulsions in adult and pediatric patients receivingcyclosporine, particularly in combination with high-dose methylprednisolone.Encephalopathy, including Posterior Reversible Encephalopathy Syndrome (PRES), hasbeen described both in postmarketing reports and in the literature. Manifestationsinclude impaired consciousness, convulsions, visual disturbances (including blindness),loss of motor function, movement disorders, and psychiatric disturbances. In manycases, changes in the white matter have been detected using imaging techniques andpathologic specimens. Predisposing factors such as hypertension, hypomagnesemia,hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations,and graft-versus-host disease have been noted in many but not all of the reportedcases. The changes in most cases have been reversible upon discontinuation ofcyclosporine, and in some cases, improvement was noted after reduction of dose. Itappears that patients receiving liver transplant are more susceptible to encephalopathythan those receiving kidney transplant. Another rare manifestation of cyclosporine-induced neurotoxicity is optic disc edema, including papilloedema, with possible visualimpairment, secondary to benign intracranial hypertension.Specific ExcipientsAnaphylactic ReactionsRarely (approximately 1 in 1000), patients receiving Sandimmune Injection (cyclosporineinjection, USP) have experienced anaphylactic reactions. Although the exact cause ofthese reactions is unknown, it is believed to be due to the Cremophor EL(polyoxyethylated castor oil) used as the vehicle for the intravenous (IV) formulation.These reactions can consist of flushing of the face and upper thorax, andnoncardiogenic pulmonary edema, with acute respiratory distress, dyspnea, wheezing,blood pressure changes, and tachycardia. One patient died after respiratory arrest and

aspiration pneumonia. In some cases, the reaction subsided after the infusion wasstopped.Patients receiving Sandimmune Injection (cyclosporine injection, USP) shouldbe under continuous observation for at least the first 30 minutes followingthe start of the infusion and at frequent intervals thereafter. If anaphylaxisoccurs, the infusion should be stopped. An aqueous solution of epinephrine1:1000 should be available at the bedside as well as a source of oxygen.Anaphylactic reactions have not been reported with the soft gelatin capsules or oralsolution which lack Cremophor EL (polyoxyethylated castor oil). In fact, patientsexperiencing anaphylactic reactions have been treated subsequently with the soft gelatincapsules or oral solution without incident.Alcohol (ethanol)The alcohol content (see DESCRIPTION) of Sandimmune should be taken into accountwhen given to patients in whom alcohol intake should be avoided or minimized, e.g.pregnant or breastfeeding women, in patients presenting with liver disease or epilepsy,in alcoholic patients, or pediatric patients. For an adult weighing 70 kg, the maximumdaily oral dose would deliver about 1 gram of alcohol which is approximately 6% of theamount of alcohol contained in a standard drink. The daily intravenous dose woulddeliver approximately 15% of the amount of alcohol contained in a standard drink.Care should be taken in using Sandimmune (cyclosporine) with nephrotoxic drugs (seePRECAUTIONS).Conversion from Neoral to SandimmuneBecause Sandimmune (cyclosporine) is not bioequivalent to Neoral, conversion fromNeoral to Sandimmune (cyclosporine) using a 1:1 ratio (mg/kg/day) may result in a lowercyclosporine blood concentration. Conversion from Neoral to Sandimmune(cyclosporine) should be made with increased blood concentration monitoring to avoidthe potential of underdosing.

PRECAUTIONS

GeneralPatients with malabsorption may have difficulty in achieving therapeutic concentrationswith Sandimmune Soft Gelatin Capsules or Oral Solution.HypertensionHypertension is a common side effect of Sandimmune (cyclosporine) therapy (seeADVERSE REACTIONS). Mild or moderate hypertension is more frequently encounteredthan severe hypertension and the incidence decreases over time. Antihypertensivetherapy may be required. Control of blood pressure can be accomplished with any ofthe common antihypertensive agents. However, since cyclosporine may causehyperkalemia, potassium-sparing diuretics should not be used. While calciumantagonists can be effective agents in treating cyclosporine-associated hypertension,care should be taken since interference with cyclosporine metabolism may require adosage adjustment (see Drug Interactions).VaccinationDuring treatment with Sandimmune (cyclosporine), vaccination may be less effective andthe use of live attenuated vaccines should be avoided.

Information for PatientsPatients should be advised that any change of cyclosporine formulationshould be made cautiously and only under physician supervision because itmay result in the need for a change in dosage.Patients should be informed of the necessity of repeated laboratory tests while they arereceiving the drug. They should be given careful dosage instructions, advised of thepotential risks during pregnancy, and informed of the increased risk of neoplasia.

Patients using cyclosporine oral solution with its accompanying syringe for dosagemeasurement should be cautioned not to rinse the syringe either before or after use.Introduction of water into the product by any means will cause variation in dose.

Laboratory TestsRenal and liver functions should be assessed repeatedly by measurement of BUN,serum creatinine, serum bilirubin, and liver enzymes.

Drug InteractionsA. Effect of Drugs and Other Agents on Cyclosporine Pharmacokineticsand/or SafetyAll of the individual drugs cited below are well substantiated to interact with cyclosporine.In addition, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) withcyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction.Caution should be exercised when using other drugs which are known to impair renalfunction (see WARNINGS, Nephrotoxicity).Drugs That May Potentiate Renal Dysfunction

Antibiotics AntineoplasticAntifungals

Anti-InflammatoryDrugs

GastrointestinalAgents ImmunosuppressivesOther Drugs

ciprofloxacin melphalan amphotericinB

azapropazon cimetidine tacrolimus fibric acidderivatives(e.g.,bezafibrate,fenofibrate)

gentamicin ketoconazolecolchicine ranitidine methotrexatetobramycin diclofenactrimethoprim with sulfamethoxazole

naproxen

vancomycin sulindac

During the concomitant use of a drug that may exhibit additive or synergistic renalimpairment potential with cyclosporine, close monitoring of renal function (in particularserum creatinine) should be performed. If a significant impairment of renal functionoccurs, reduction in the dosage of cyclosporine and/or coadministered drug or analternative treatment should be considered.Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4,and is a substrate of the multidrug efflux transporter P-glycoprotein. Various agents areknown to either increase or decrease plasma or whole blood concentrations ofcyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein transporteror both. Compounds that decrease cyclosporine absorption, such as orlistat, should beavoided. Appropriate Sandimmune (cyclosporine) dosage adjustment to achieve thedesired cyclosporine concentrations is essential when drugs that significantly altercyclosporine concentrations are used concomitantly (see DOSAGE ANDADMINISTRATION, Blood Concentration Monitoring). 1. Drugs That Increase Cyclosporine Concentrations

CalciumChannelBlockers

Antifungals Antibiotics Glucocorticoids Other Drugs

diltiazem fluconazole azithromycin methylprednisoloneallopurinolnicardipineitraconazole clarithromycin amiodaroneverapamil ketoconazoleerythromycin bromocriptine

voriconazole quinupristin/ colchicine

dalfopristindanazolimatinibmetoclopramidenefazodoneoralcontraceptives

HIV Protease inhibitorsThe HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) areknown to inhibit cytochrome P-450 3A and thus could potentially increase theconcentrations of cyclosporine, however, no formal studies of the interaction areavailable. Care should be exercised when these drugs are administered concomitantly.Grapefruit juiceGrapefruit and grapefruit juice affect metabolism, increasing blood concentrations ofcyclosporine, thus should be avoided. 2. Drugs/Dietary Supplements That Decrease CyclosporineConcentrations

AntibioticsAnticonvulsants

Other Drugs/ DietarySupplements

nafcillin carbamazepine bosentan St.John’sWort

rifampin oxcarbazepine octreotidephenobarbital orlistatphenytoin sulfinpyrazone

terbinafineticlopidine

BosentanCo-administration of bosentan (250 to 1000 mg every 12 hours based on tolerability)and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a C of200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in thecyclosporine mean dose-normalized AUC, C , and trough concentration ofapproximately 50%, 30% and 60%, respectively, compared to when cyclosporine wasgiven alone (see also Effect of Cyclosporine on the Pharmacokinetics and/or Safety ofOther Drugs or Agents). Coadministration of cyclosporine with bosentan should beavoided.BoceprevirCoadministration of boceprevir (800 mg three times daily for 7 days) and cyclosporine(100 mg single dose) in healthy subjects resulted in increases in the mean AUC and Cof cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to whencyclosporine was given alone.TelaprevirCoadministration of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10mg on Day 8) in healthy subjects resulted in increases in the mean dose-normalized AUCand C of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared towhen cyclosporine (100 mg single dose) was given alone.St. John’s WortThere have been reports of a serious drug interaction between cyclosporine and theherbal dietary supplement, St. John’s Wort. This interaction has been reported toproduce a marked reduction in the blood concentrations of cyclosporine, resulting insubtherapeutic levels, rejection of transplanted organs, and graft loss.

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subtherapeutic levels, rejection of transplanted organs, and graft loss.RifabutinRifabutin is known to increase the metabolism of other drugs metabolized by thecytochrome P-450 system. The interaction between rifabutin and cyclosporine has notbeen studied. Care should be exercised when these two drugs are administeredconcomitantly.B. Effect of Cyclosporine on the Pharmacokinetics and/or Safety of OtherDrugs or AgentsCyclosporine is an inhibitor of CYP3A4 and of multiple drug efflux transporters (e.g., P-glycoprotein) and may increase plasma concentrations of comedications that aresubstrates of CYP3A4, P-glycoprotein, or organic anion transporter proteins.Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoAreductase inhibitors (statins) and aliskiren, bosentan, dabigatran, repaglinide, NSAIDs,sirolimus, etoposide, and other drugs.See the full prescribing information of the other drug for further information and specificrecommendations. The decision on coadministration of cyclosporine with other drugs oragents should be made by the healthcare provider following the careful assessment ofbenefits and risks.

DigoxinSevere digitalis toxicity has been seen within days of starting cyclosporine in severalpatients taking digoxin. If digoxin is used concurrently with cyclosporine, serum digoxinconcentrations should be monitored.ColchicineThere are reports on the potential of cyclosporine to enhance the toxic effects ofcolchicine, such as myopathy and neuropathy, especially in patients with renaldysfunction. Concomitant administration of cyclosporine and colchicine results insignificant increases in colchicine plasma concentrations. If colchicine is usedconcurrently with cyclosporine, a reduction in the dosage of colchicine is recommended.HMG Co-A reductase inhibitors (statins)Literature and postmarketing cases of myotoxicity, including muscle pain and weakness,myositis, and rhabdomyolysis, have been reported with concomitant administration ofcyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely,fluvastatin. When concurrently administered with cyclosporine, the dosage of thesestatins should be reduced according to label recommendations. Statin therapy needs tobe temporarily withheld or discontinued in patients with signs and symptoms ofmyopathy or those with risk factors predisposing to severe renal injury, including renalfailure, secondary to rhabdomyolysis.RepaglinideCyclosporine may increase the plasma concentrations of repaglinide and therebyincrease the risk of hypoglycemia. In 12 healthy male subjects who received two dosesof 100 mg cyclosporine capsule orally 12 hours apart with a single dose of 0.25 mgrepaglinide tablet (one half of a 0.5 mg tablet) orally 13 hours after the cyclosporineinitial dose, the repaglinide mean C and AUC were increased 1.8 fold (range, 0.6 to3.7 fold) and 2.4 fold (range, 1.2 to 5.3 fold), respectively. Close monitoring of bloodglucose level is advisable for a patient taking cyclosporine and repaglinide concomitantly.AmbrisentanCoadministration of ambrisentan (5 mg daily) and cyclosporine (100 to 150 mg twicedaily initially, then dosing to achieve C 150 to 200 ng/mL) for 8 days in healthysubjects resulted mean increases in ambrisentan AUC and C of approximately 2-foldand 1.5-fold, respectively, compared to ambrisentan alone. When coadministeringambrisentan with cyclosporine, the ambrisentan dose should not be titrated to therecommended maximum daily dose.Anthracycline antibioticsHigh doses of cyclosporine (e.g., at starting intravenous dose of 16 mg/kg/day) may

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increase the exposure to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone,daunorubicin) in cancer patients.AliskirenCyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein andCYP3A4. In 14 healthy subjects who received concomitantly single doses of cyclosporine(200 mg) and reduced dose aliskiren (75 mg), the mean C of aliskiren was increasedby approximately 2.5-fold (90% CI: 1.96 to 3.17) and the mean AUC by approximately4.3 fold (90% CI: 3.52 to 5.21), compared to when these subjects received aliskirenalone. The concomitant administration of aliskiren with cyclosporine prolonged themedian aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the T (0.5hours versus 1.5 to 2.0 hours). The mean AUC and C of cyclosporine werecomparable to reported literature values. Coadministration of cyclosporine and aliskirenin these subjects also resulted in an increase in the number and/or intensity of adverseevents, mainly headache, hot flush, nausea, vomiting, and somnolence. Thecoadministration of cyclosporine with aliskiren is not recommended.BosentanIn healthy subjects, coadministration of bosentan and cyclosporine resulted in time-dependent mean increases in dose-normalized bosentan trough concentrations (i.e.,approximately 21-fold on Day 1 and 2-fold on Day 8 (steady state)) compared to whenbosentan was given alone as a single dose on Day 1 (see also Effect of Drugs and OtherAgents on Cyclosporine Pharmacokinetics and/or Safety). Coadministration ofcyclosporine with bosentan should be avoided.DabigatranThe effect of cyclosporine on dabigatran concentrations had not been formally studied.Concomitant administration of dabigatran and cyclosporine may result in increasedplasma dabigatran concentrations due to the P-gp inhibitory activity of cyclosporine.Coadministration of cyclosporine with dabigatran should be avoided.Potassium sparing diureticsCyclosporine should not be used with potassium-sparing diuretics because hyperkalemiacan occur. Caution is also required when cyclosporine is coadministered with potassium-sparing drugs (e.g., angiotensin-converting enzyme inhibitors, angiotensin II receptorantagonists), potassium-containing drugs as well as in patients on a potassium-rich diet.Control of potassium levels in these situations is advisable.Nonsteroidal Anti-inflammatory Drug (NSAID) InteractionsClinical status and serum creatinine should be closely monitored when cyclosporine isused with NSAIDs in rheumatoid arthritis patients (see WARNINGS).Pharmacodynamic interactions have been reported to occur between cyclosporine andboth naproxen and sulindac, in that concomitant use is associated with additivedecreases in renal function, as determined by Tc-diethylenetriaminepenta acetic acid(DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant administrationof diclofenac does not affect blood concentrations of cyclosporine, it has beenassociated with approximate doubling of diclofenac blood levels and occasional reportsof reversible decreases in renal function. Consequently, the dose of diclofenac should bein the lower end of the therapeutic range.Methotrexate InteractionPreliminary data indicate that when methotrexate and cyclosporine were coadministeredto rheumatoid arthritis patients (N = 20), methotrexate concentrations (AUCs) wereincreased approximately 30% and the concentrations (AUCs) of its metabolite, 7-hydroxy methotrexate, were decreased by approximately 80%. The clinical significanceof this interaction is not known. Cyclosporine concentrations do not appear to havebeen altered (N = 6).SirolimusElevations in serum creatinine were observed in studies using sirolimus in combinationwith full-dose cyclosporine. This effect is often reversible with cyclosporine dosereduction. Simultaneous coadministration of cyclosporine significantly increases blood

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levels of sirolimus. To minimize increases in sirolimus blood concentrations, it isrecommended that sirolimus be given 4 hours after cyclosporine administration.NifedipineFrequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine hasbeen reported. The concomitant use of nifedipine should be avoided in patients in whomgingival hyperplasia develops as a side effect of cyclosporine.MethylprednisoloneConvulsions when high dose methylprednisolone is given concomitantly withcyclosporine have been reported.Other Immunosuppressive Drugs and AgentsPsoriasis patients receiving other immunosuppressive agents or radiation therapy(including PUVA and UVB) should not receive concurrent cyclosporine because of thepossibility of excessive immunosuppression.C. Effect of Cyclosporine on the Efficacy of Live VaccinesDuring treatment with cyclosporine, vaccination may be less effective. The use of livevaccines should be avoided.For additional information on Cyclosporine Drug Interactions please contact NovartisMedical Affairs Department at 1-888-NOW-NOVA (1-888-669-6682).

Carcinogenesis, Mutagenesis, and Impairment of FertilityCyclosporine gave no evidence of mutagenic or teratogenic effects in appropriate testsystems. Only at dose levels toxic to dams, were adverse effects seen in reproductionstudies in rats (see Pregnancy).Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statisticallysignificant trend was found for lymphocytic lymphomas in females, and the incidence ofhepatocellular carcinomas in mid-dose males significantly exceeded the control value. Inthe 24-month rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic isletcell adenomas significantly exceeded the control rate in the low-dose level.The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.No impairment in fertility was demonstrated in studies in male and female rats.Cyclosporine has not been found mutagenic/genotoxic in the Ames test, the V79-HGPRTTest, the micronucleus test in mice and Chinese hamsters, the chromosome-aberrationtests in Chinese hamster bone marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatidexchange (SCE) induction by cyclosporine using human lymphocytes in vitro gaveindication of a positive effect (i.e., induction of SCE), at high concentrations in thissystem. In two published research studies, rabbits exposed to cyclosporine in utero (10mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renalhypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeksof age. Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twicethe recommended human intravenous dose) had fetuses with an increased incidence ofventricular septal defect. These findings have not been demonstrated in other speciesand their relevance for humans is unknown.An increased incidence of malignancy is a recognized complication ofimmunosuppression in recipients of organ transplants. The most common forms ofneoplasms are non-Hodgkin’s lymphoma and carcinomas of the skin. The risk ofmalignancies in cyclosporine recipients is higher than in the normal, healthy population,but similar to that in patients receiving other immunosuppressive therapies. It has beenreported that reduction or discontinuance of immunosuppression may cause the lesionsto regress.

Pregnancy

Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gaveno evidence of mutagenic or teratogenic effects in the standard test systems with oralapplication (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally).Sandimmune Oral Solution (cyclosporine oral solution, USP) has been shown to beembryo- and fetotoxic in rats and rabbits when given in doses 2-5 times the humandose. At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day), SandimmuneOral Solution (cyclosporine oral solution, USP) was embryo- and fetotoxic as indicatedby increased pre- and postnatal mortality and reduced fetal weight together with relatedskeletal retardations. In the well-tolerated dose range (rats at up to 17 mg/kg/day andrabbits at up to 30 mg/kg/day), Sandimmune Oral Solution (cyclosporine oral solution,USP) proved to be without any embryolethal or teratogenic effects.There are no adequate and well-controlled studies in pregnant women and therefore,Sandimmune (cyclosporine) should not be used during pregnancy unless the potentialbenefit to the mother justifies the potential risk to the fetus.In pregnant transplant recipients who are being treated with immunosuppressants, therisk of premature birth is increased. The following data represent the reported outcomesof 116 pregnancies in women receiving Sandimmune (cyclosporine) during pregnancy,90% of whom were transplant patients, and most of whom received Sandimmune(cyclosporine) throughout the entire gestational period. Since most of the patients werenot prospectively identified, the results are likely to be biased toward negative outcomes.The only consistent patterns of abnormality were premature birth (gestational period of28 to 36 weeks) and low-birth weight for gestational age. It is not possible to separatethe effects of Sandimmune (cyclosporine) on these pregnancies from the effects of theother immunosuppressants, the underlying maternal disorders, or other aspects of thetransplantation milieu. Sixteen fetal losses occurred. Most of the pregnancies (85 of100) were complicated by disorders; including, preeclampsia, eclampsia, prematurelabor, abruptio placentae, oligohydramnios, Rh incompatibility, and feto-placentaldysfunction. Preterm delivery occurred in 47%. Seven malformations were reported in 5viable infants and in 2 cases of fetal loss. Twenty-eight percent of the infants were smallfor gestational age. Neonatal complications occurred in 27%. In a report of 23 childrenfollowed up to 4 years, postnatal development was said to be normal. More informationon cyclosporine use in pregnancy is available from Novartis PharmaceuticalsCorporation.A limited number of observations in children exposed to cyclosporine in utero areavailable, up to an age of approximately 7 years. Renal function and blood pressure inthese children were normal.The alcohol content of the Sandimmune formulations should also be taken into accountin pregnant women (see WARNINGS, Special Excipients).

Nursing MothersCyclosporine is present in breast milk. Because of the potential for serious adverse drugreactions in nursing infants from Sandimmune, a decision should be made whether todiscontinue nursing or to discontinue the drug, taking into account the importance ofthe drug to the mother. Sandimmune contains ethanol. Ethanol will be present in humanmilk at levels similar to that found in maternal serum and if present in breast milk will beorally absorbed by a nursing infant (see WARNINGS).

Pediatric UseAlthough no adequate and well-controlled studies have been conducted in children,patients as young as 6 months of age have received the drug with no unusual adverseeffects.

Geriatric UseClinical studies of Sandimmune (cyclosporine) did not include sufficient numbers ofsubjects aged 65 and over to determine whether they respond differently from youngerpatients. Other reported clinical experience has not identified differences in responsesbetween the elderly and younger patients. In general, dose selection for an elderly

between the elderly and younger patients. In general, dose selection for an elderlypatient should be cautious, usually starting at the low end of the dosing range, reflectingthe greater frequency of decreased hepatic, renal, or cardiac function, and ofconcomitant disease or other drug therapy.

ADVERSE REACTIONSThe principal adverse reactions of Sandimmune (cyclosporine) therapy are renaldysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.HypertensionHypertension, which is usually mild to moderate, may occur in approximately 50% ofpatients following renal transplantation and in most cardiac transplant patients.Glomerular Capillary ThrombosisGlomerular capillary thrombosis has been found in patients treated with cyclosporineand may progress to graft failure. The pathologic changes resemble those seen in thehemolytic-uremic syndrome and include thrombosis of the renal microvasculature, withplatelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles,microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function.Similar findings have been observed when other immunosuppressives have beenemployed post transplantation.HypomagnesemiaHypomagnesemia has been reported in some, but not all, patients exhibiting convulsionswhile on cyclosporine therapy. Although magnesium-depletion studies in normal subjectssuggest that hypomagnesemia is associated with neurologic disorders, multiple factors,including hypertension, high-dose methylprednisolone, hypocholesterolemia, andnephrotoxicity associated with high plasma concentrations of cyclosporine appear to berelated to the neurological manifestations of cyclosporine toxicity.Clinical StudiesThe following reactions occurred in 3% or greater of 892 patients involved in clinical trialsof kidney, heart, and liver transplants:

Randomized KidneyPatients

All Sandimmune(cyclosporine) Patients

SandimmuneAzathioprine Kidney Heart LiverBody System/ (N = 227) (N = 228) (N = 705) (N = 112) (N = 75) AdverseReactions % % % % %Genitourinary Renal Dysfunction 32 6 25 38 37Cardiovascular Hypertension 26 18 13 53 27 Cramps 4 < 1 2 < 1 0Skin Hirsutism 21 < 1 21 28 45 Acne 6 8 2 2 1Central NervousSystem Tremor 12 0 21 31 55 Convulsions 3 1 1 4 5 Headache 2 < 1 2 15 4Gastrointestinal Gum Hyperplasia 4 0 9 5 16 Diarrhea 3 < 1 3 4 8 Nausea/Vomiting 2 < 1 4 10 4 Hepatotoxicity < 1 < 1 4 7 4 Abdominal

Discomfort < 1 0 < 1 7 0Autonomic NervousSystem Paresthesia 3 0 1 2 1 Flushing < 1 0 4 0 4Hematopoietic Leukopenia 2 19 < 1 6 0 Lymphoma < 1 0 1 6 1Respiratory Sinusitis < 1 0 4 3 7Miscellaneous Gynecomastia < 1 0 < 1 4 3

The following reactions occurred in 2% or less of patients: allergic reactions, anemia,anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearingloss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus.The following reactions occurred rarely: anxiety, chest pain, constipation, depression,hair breaking, hematuria, joint pain, lethargy, mouth sores, myocardial infarction, nightsweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visualdisturbance, weakness, weight loss.

Sandimmune (cyclosporine) was discontinued on a temporary basis and then restartedin 18 additional patients.

Renal Transplant Patients in Whom Therapy Was DiscontinuedRandomized Patients All Sandimmune

PatientsSandimmune Azathioprine

(N = 227) (N = 228) (N = 705)Reason for Discontinuation % % %Renal Toxicity 5.7 0 5.4Infection 0 0.4 0.9Lack of Efficacy 2.6 0.9 1.4Acute Tubular Necrosis 2.6 0 1.0Lymphoma/LymphoproliferativeDisease 0.4 0 0.3Hypertension 0 0 0.3Hematological Abnormalities 0 0.4 0Other 0 0 0.7

Patients receiving immunosuppressive therapies, including cyclosporine andcyclosporine-containing regimens, are at increased risk of infections (viral, bacterial,fungal, and parasitic). Both generalized and localized infections can occur. Preexistinginfections may also be aggravated. Fatal outcomes have been reported (seeWARNINGS).

Infectious Complications in the Randomized Renal Transplant PatientsSandimmune Treatment Standard Treatment*

(N = 227) (N = 228)Complication % of Complications % of ComplicationsSepticemia 5.3 4.8Abscesses 4.4 5.3Systemic Fungal Infection 2.2 3.9Local Fungal Infection 7.5 9.6Cytomegalovirus 4.8 12.3Other Viral Infections 15.9 18.4Urinary Tract Infections 21.1 20.2Wound and Skin Infections 7.0 10.1

*Some patients also received ALG.Pneumonia 6.2 9.2

Cremophor EL (polyoxyethylated castor oil) is known to cause hyperlipemia andelectrophoretic abnormalities of lipoproteins. These effects are reversible upondiscontinuation of treatment but are usually not a reason to stop treatment.

Postmarketing ExperienceHepatotoxicityCases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, andliver failure; serious and/or fatal outcomes have been reported (see WARNINGS,Hepatotoxicity).Increased Risk of InfectionsCases of JC virus-associated progressive multifocal leukoencephalopathy (PML),sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virusresulting in graft loss have been reported (see WARNINGS, Polyoma Virus Infection).Headache, Including MigraineCases of migraine have been reported. In some cases, patients have been unable tocontinue cyclosporine, however, the final decision on treatment discontinuation shouldbe made by the treating physician following the careful assessment of benefits versusrisks.Pain of Lower ExtremitiesIsolated cases of pain of lower extremities have been reported in association withcyclosporine. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.

OVERDOSAGEThere is a minimal experience with overdosage. Because of the slow absorption ofSandimmune Soft Gelatin Capsules or Oral Solution, forced emesis and gastric lavagewould be of value up to 2 hours after administration. Transient hepatotoxicity andnephrotoxicity may occur which should resolve following drug withdrawal. Oral doses ofcyclosporine up to 10 g (about 150 mg/kg) have been tolerated with relatively minorclinical consequences, such as vomiting, drowsiness, headache, tachycardia, and in afew patients, moderately severe, reversible impairment of renal function. However,serious symptoms of intoxication have been reported following accidental parenteraloverdosage with cyclosporine in premature neonates. General supportive measures andsymptomatic treatment should be followed in all cases of overdosage. Sandimmune(cyclosporine) is not dialyzable to any great extent, nor is it cleared well by charcoalhemoperfusion. The oral LD is 2329 mg/kg in mice, 1480 mg/kg in rats, and >1000 mg/kg in rabbits. The intravenous (IV) LD is 148 mg/kg in mice, 104 mg/kg inrats, and 46 mg/kg in rabbits.

DOSAGE AND ADMINISTRATION

Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) andSandimmune Oral Solution (cyclosporine oral solution, USP)Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune OralSolution (cyclosporine oral solution, USP) have decreased bioavailability in comparison toNeoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral OralSolution (cyclosporine oral solution, USP) MODIFIED. Sandimmune and Neoral are notbioequivalent and cannot be used interchangeably without physician supervision.The initial oral dose of Sandimmune (cyclosporine) should be given 4 to 12 hours prior totransplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to18 mg/kg was used in most clinical trials, few centers continue to use the highest dose,most favoring the lower end of the scale. There is a trend towards use of even lower

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initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initialsingle daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5%per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfullytapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplantpatients without an apparent rise in rejection rate.See Blood Concentration Monitoring, below.Specific PopulationsRenal ImpairmentCyclosporine undergoes minimal renal elimination and its pharmacokinetics do notappear to be significantly altered in patients with end-stage renal disease who receiveroutine hemodialysis treatments (see CLINICAL PHARMACOLOGY). However, due to itsnephrotoxic potential (see WARNINGS), careful monitoring of renal function isrecommended; cyclosporine dosage should be reduced if indicated (see WARNINGS andPRECAUTIONS).Hepatic ImpairmentThe clearance of cyclosporine may be significantly reduced in severe liver diseasepatients (see CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patientswith severe liver impairment to maintain blood concentrations within the recommendedtarget range (see WARNINGS and PRECAUTIONS).PediatricsIn pediatric usage, the same dose and dosing regimen may be used as in adultsalthough in several studies, children have required and tolerated higher doses thanthose used in adults.Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosageschedules of prednisone appear to achieve similar results. A dosage schedule based onthe patient’s weight started with 2.0 mg/kg/day for the first 4 days tapered to1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Another centerstarted with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day.After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustmentsin dosage of prednisone must be made according to the clinical situation.To make Sandimmune Oral Solution (cyclosporine oral solution, USP) more palatable, theoral solution may be diluted with milk, chocolate milk, or orange juice preferably at roomtemperature. Patients should avoid switching diluents frequently. Sandimmune SoftGelatin Capsules and Oral Solution should be administered on a consistent schedule withregard to time of day and relation to meals.Take the prescribed amount of Sandimmune (cyclosporine) from the container using thedosage syringe supplied after removal of the protective cover, and transfer the solutionto a glass of milk, chocolate milk, or orange juice. Stir well and drink at once. Do notallow to stand before drinking. It is best to use a glass container and rinse it with morediluent to ensure that the total dose is taken. After use, replace the dosage syringe inthe protective cover. Do not rinse the dosage syringe with water or other cleaningagents either before or after use. If the dosage syringe requires cleaning, it must becompletely dry before resuming use. Introduction of water into the product by anymeans will cause variation in dose.

Sandimmune Injection (cyclosporine injection, USP)FOR INFUSION ONLYNote: Anaphylactic reactions have occurred with Sandimmune Injection (cyclosporineinjection, USP). See WARNINGS.Patients unable to take Sandimmune Soft Gelatin Capsules or Oral Solution pre- orpostoperatively may be treated with the intravenous (IV) concentrate. SandimmuneInjection (cyclosporine injection, USP) is administered at 1/3 the oral dose.The initial dose of Sandimmune Injection (cyclosporine injection, USP) should be given 4to 12 hours prior to transplantation as a single intravenous dose of 5 to 6 mg/kg/day.This daily single dose is continued postoperatively until the patient can tolerate the soft

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This daily single dose is continued postoperatively until the patient can tolerate the softgelatin capsules or oral solution. Patients should be switched to Sandimmune SoftGelatin Capsules or Oral Solution as soon as possible after surgery. In pediatric usage,the same dose and dosing regimen may be used, although higher doses may berequired.Adjunct steroid therapy is to be used (See aforementioned).Immediately before use, the intravenous concentrate should be diluted 1 mLSandimmune Injection (cyclosporine injection, USP) in 20 mL to 100 mL 0.9% SodiumChloride Injection or 5% Dextrose Injection and given in a slow intravenous infusion overapproximately 2 to 6 hours.Diluted infusion solutions should be discarded after 24 hours.The Cremophor EL (polyoxyethylated castor oil) contained in the concentrate forintravenous infusion can cause phthalate stripping from PVC.Parenteral drug products should be inspected visually for particulate matter anddiscoloration prior to administration, whenever solution and container permit.

Blood Concentration MonitoringSeveral study centers have found blood concentration monitoring of cyclosporine usefulin patient management. While no fixed relationships have yet been established, in oneseries of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted toachieve specific whole blood 24-hour trough concentrations of 100 to 200 ng/mL asdetermined by high-pressure liquid chromatography (HPLC).Of major importance to blood concentration analysis is the type of assay used. Theabove concentrations are specific to the parent cyclosporine molecule and correlatedirectly to the new monoclonal specific radioimmunoassays (mRIA-sp). Nonspecificassays are also available which detect the parent compound molecule and various of itsmetabolites. Older studies often cited concentrations using a nonspecific assay whichwere roughly twice those of specific assays. Assay results are not interchangeable andtheir use should be guided by their approved labeling. If plasma specimens areemployed, concentrations will vary with the temperature at the time of separation fromwhole blood. Plasma concentrations may range from 1/2 to 1/5 of whole bloodconcentrations. Refer to individual assay labeling for complete instructions. In addition,Transplantation Proceedings (June 1990) contains position papers and a broadconsensus generated at the Cyclosporine-Therapeutic Drug Monitoring conference thatyear. Blood concentration monitoring is not a replacement for renal function monitoringor tissue biopsies.

HOW SUPPLIEDSandimmune Soft Gelatin Capsules (cyclosporine capsules, USP)

25 mg: Oval, pink, branded “ 78/240”. Unit dose packages of 30 capsules, 3 blister cards of 10capsules………………………………………………………….NDC 0078-0240-15

100 mg: Oblong, dusty rose, branded “ 78/241”. Unit dose packages of 30capsules, 3 blister cards of 10capsules………………………………………………………….NDC 0078-0241-15Store and Dispense: Store at 20°C to 25°C (68°F to 77°F); excursions permittedbetween 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].An odor may be detected upon opening the unit dose container, which will dissipateshortly thereafter. This odor does not affect the quality of the product.Sandimmune Oral Solution (cyclosporine oral solution, USP)Supplied in 50 mL bottles containing 100 mg of cyclosporine per mL NDC 0078-0110-22

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A dosage syringe is provided for dispensing.Store and Dispense: In the original container at temperatures below 30°C (86°F). Donot store in the refrigerator. Protect from freezing. Once opened, the contents must beused within 2 months.Sandimmune Injection (cyclosporine injection, USP)FOR INTRAVENOUS INFUSIONSupplied as a 5 mL sterile ampul containing 50 mg of cyclosporine per mL, in boxes of 10ampuls…………………………………………………………………..NDC 0078-0109-01Store and Dispense: At temperatures below 30°C (86°F). Protect from light.FOR INFUSION ONLY*Cremophor is the registered trademark of BASF Aktiengesellschaft.Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936© NovartisRevised: June 2021T2021-83

PRINCIPAL DISPLAY PANELNDC 0078-0240-1525 mg30 SOFT GELATIN CAPSULESSANDIMMUNE Soft Gelatin Capsules(cyclosporine capsules, USP)Each 25 mg capsule contains:cyclosporine, USP 25 mgalcohol, USP dehydrated max 12.7% by volumeInactive Ingredients: corn oil, gelatin, iron oxide red, linoleoyl macrogolglycerides,sorbitol, and titanium dioxide. May also contain glycerol.WARNING: Sandimmune (cyclosporine capsules, USP) isNOT BIOEQUIVALENT to Neoral (cyclosporine capsules, USP) MODIFIED.Do NOT use interchangeably without a physician’s supervision.Dosage:See package insert for dosage information.Rx onlyNOVARTIS

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PRINCIPAL DISPLAY PANELNDC 0078-0241-15100 mg30 SOFT GELATIN CAPSULESSANDIMMUNE Soft Gelatin Capsules(cyclosporine capsules, USP)Each 100 mg capsule contains:cyclosporine, USP 100 mgalcohol, USP dehydrated max 12.7% by volumeInactive Ingredients: corn oil, gelatin, iron oxide red, linoleoyl macrogolglycerides,sorbitol, and titanium dioxide. May also contain glycerol or iron oxide yellow.

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WARNING: Sandimmune (cyclosporine capsules, USP) isNOT BIOEQUIVALENT to Neoral (cyclosporine capsules, USP) MODIFIED.Do NOT use interchangeably without a physician’s supervision.Dosage:See package insert for dosage information.Rx onlyNOVARTIS

PRINCIPAL DISPLAY PANELRx Only NDC 0078-0110-22SANDIMMUNE Oral Solution(cyclosporine oral solution, USP)100 mg/mL

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WARNING: Sandimmune (oral solution, USP) isNOT BIOEQUIVALENT to Neoral (cyclosporine oral solution, USP) MODIFIED.Do NOT use interchangeably without a physician’s supervision.Each mL contains:cyclosporine, USP 100 mgdehydrated alcohol, Ph. Helv 12.5%

PRINCIPAL DISPLAY PANELRx Only NDC 0078-0109-01SANDIMMUNE Injection(cyclosporine injection, USP)Sterile solution for intravenous infusion onlyEach mL contains:cyclosporine, USP 50 mgFOR INFUSION ONLY. DILUTE BEFORE USE.250 mg (5 mL ampul) 10 Ampuls

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SANDIMMUNE cyclosporine capsule, liquid filled

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0078-0240

Route of Administration ORAL

Active Ingredient/Active MoietyIngredient Name Basis of Strength Strength

CYCLOSPORINE (UNII: 83HN0GTJ6D) (CYCLOSPORINE - UNII:83HN0GTJ6D) CYCLOSPORINE 25 mg

Inactive IngredientsIngredient Name Strength

ALCOHOL (UNII: 3K9958V90M) GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) OLIVE OIL (UNII: 6UYK2W1W1E)

FERRIC OXIDE RED (UNII: 1K09F3G675) SORBITOL (UNII: 506T60A25R) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) CORN OIL (UNII: 8470G57WFM) CASTOR OIL (UNII: D5340Y2I9G)

Product CharacteristicsColor PINK (pink) Score no scoreShape OVAL (Oblong) Size 11mmFlavor Imprint Code 78;240Contains

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:0078-0240-

15 30 in 1 PACKAGE 03/02/1990

1 NDC:0078-0240-61

1 in 1 BLISTER PACK; Type 0: Not a CombinationProduct

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

NDA NDA050625 03/02/1990

SANDIMMUNE cyclosporine capsule, liquid filled

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0078-0241

Route of Administration ORAL

Active Ingredient/Active MoietyIngredient Name Basis of Strength Strength

CYCLOSPORINE (UNII: 83HN0GTJ6D) (CYCLOSPORINE - UNII:83HN0GTJ6D) CYCLOSPORINE 100 mg

Inactive IngredientsIngredient Name Strength

ALCOHOL (UNII: 3K9958V90M) GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) CORN OIL (UNII: 8470G57WFM) FERRIC OXIDE RED (UNII: 1K09F3G675) SORBITOL (UNII: 506T60A25R) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) CASTOR OIL (UNII: D5340Y2I9G) OLIVE OIL (UNII: 6UYK2W1W1E)

Product CharacteristicsColor RED (dusty rose) Score no scoreShape CAPSULE (Oblong) Size 25mmFlavor Imprint Code 78;241Contains

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:0078-0241-

15 30 in 1 PACKAGE 03/02/1990

1 NDC:0078-0241-61

1 in 1 BLISTER PACK; Type 0: Not a CombinationProduct

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

NDA NDA050625 03/02/1990

SANDIMMUNE cyclosporine injection

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0078-0109

Route of Administration INTRAVENOUS

Active Ingredient/Active MoietyIngredient Name Basis of Strength Strength

CYCLOSPORINE (UNII: 83HN0GTJ6D) (CYCLOSPORINE - UNII:83HN0GTJ6D) CYCLOSPORINE 50 mg in 1 mL

Inactive IngredientsIngredient Name Strength

ALCOHOL (UNII: 3K9958V90M) NITROGEN (UNII: N762921K75) CASTOR OIL (UNII: D5340Y2I9G) 650 mg in 1 mL

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:0078-0109-

01 10 in 1 BOX 11/14/1983

1 NDC:0078-0109-61

5 mL in 1 AMPULE; Type 0: Not a CombinationProduct

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

NDA NDA050573 11/14/1983

SANDIMMUNE cyclosporine solution

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0078-0110

Route of Administration ORAL

Novartis Pharmaceuticals Corporation

Active Ingredient/Active MoietyIngredient Name Basis of Strength Strength

CYCLOSPORINE (UNII: 83HN0GTJ6D) (CYCLOSPORINE - UNII:83HN0GTJ6D) CYCLOSPORINE 100 mg in 1 mL

Inactive IngredientsIngredient Name Strength

ALCOHOL (UNII: 3K9958V90M) OLIVE OIL (UNII: 6UYK2W1W1E)

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:0078-0110-

2250 mL in 1 BOTTLE; Type 0: Not a CombinationProduct 11/14/1983

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

NDA NDA050574 11/14/1983

Labeler - Novartis Pharmaceuticals Corporation (002147023)

Revised: 6/2021